Geysen, EP 198855, disclosed a method for the simultaneous synthesis of a large number of different peptides. Basically, this method involves the synthesis of peptides on a solid polymeric surface, such as polyethylene, which may be molded into the shape of a rod or pin. In a preferred embodiment of the method, these rods or pins are positioned in a holder so that they form a 12 by 8 matrix, with the rods or pins being positioned so that the spacing corresponds to that of the wells of microtiter plates which are widely used for ELISA (enzyme-linked immunosorbent assay) tests.
Huebner et al., U.S. Pat. No. 5,182,366 (incorporated herein by reference) disclosed a method for preparing large mixtures of peptides on solid phase resins in equimolar ratios. This enables one to quickly search for compounds that bind to or react with a ligand by contacting the ligand (e.g., a bound receptor) with a set of peptide mixtures and noting which members of the set bind or react. Typically, the sets are prepared by specifying a known amino acid at one or two positions of an oligopeptide and providing mixtures of amino acids at the other positions. Thus, one peptide mixture might consist of a pool of hexapeptides of the formula Gly-Gly-X.sub.1 -X.sub.2 -X.sub.3 -X.sub.4 (SEQ. ID. No.:1), where each X indicates that all amino acids are found at that position. The next peptide mixture would be Gly-Ala-X.sub.1 -X.sub.2 -X.sub.3 -X.sub.4 (SEQ. ID. No.:2), followed by Gly-Cys-X.sub.1 -X.sub.2 -X.sub.3 -X.sub.4 (SEQ. ID. No.:3), and so forth. The set consisting of all of these mixtures is termed a "library." A library is screened by testing each individual mixture and noting which mixtures produce a positive response. In some formats, the mixtures may be screened simultaneously. The positive mixtures are then resynthesized with additional positions specified. Thus, for example, if the mixture containing Phe-Tyr-X.sub.1 -X.sub.2 -X.sub.3 -X4 (SEQ. ID. No.:4) was positive, the next mixture synthesized might be Phe-Tyr-Gly-X.sub.2 -X.sub.3 -X.sub.4 (SEQ. ID. No.:5). This process (called "deconvolution") is reiterated until individual peptides are synthesized and tested.
Bartlett et al., W091/19735, and Zuckermann et al., W094/06451 disclosed a method for extending combinatorial library synthesis to compounds other than peptides. Bartlett and Zuckermann disclosed modular compounds based on N-substituted polyamides, polycarbamates, and other backbones, which permits one to research non-peptide compounds. These libraries are also analyzed by deconvolution.